1. Field of the Invention
Embodiments of the present invention relate to compositions of polyalkylene oxide polymers, as well as methods of making and using the polymers and kits for their use. More particularly, embodiments relate to compositions comprising functionalized polyethylene glycol (PEG) in new and useful configurations as nanocarriers, nanogel particles and aggregated nanogel particles.
2. Description of the Related Art
PEG conjugation has been widely used to improve the water solubility and systemic persistence of drugs such as interferon. Typically, one PEG is conjugated to one interferon molecule resulting in a therapeutically effective drug product. This only works well for highly potent drugs since the mass of polymeric carrier in a drug product becomes prohibitively large for high dose drugs. Further, in order to improve biological properties, other agents such as cell adhesion peptides have been linked to the same types of drugs. For example, Doxorubicin has been linked to a bicyclic RGD peptide, however, this resulted in the loss of aqueous solubility (F. H. de Groot, H. J. Broxterman, H. P. H. M. Adams, A. van Vliet, G. I. Tesser, Y. W. Elderkamp, A. J. Schraa, R. J. Kok, G. Molema, H. M. Pinedo, H. W. Scheeren, Molecular Cancer Therapeutics, 2002, 1, 901-911). Also, previous attempts at increasing drug loading on polymeric carriers have only partially succeeded. For example, it was demonstrated that water solubility was lost when more than three copies of campthothecin were attached to PEG (J. J. Khandare, P. Chandna, Y. Wang, V. P. Pozharov, T. Minko, Journal of Pharm. Exper. Ther., 2006, 317, 929-937). Further, Andersson et al. demonstrated that a high molecular weight polymeric carrier capable of increasing the loading of doxorubicin could be synthesized. However, the size of the carrier was very large and the authors concluded “it became clear from the outset . . . that they do not possess the desired solubility . . . even after prolonged sonication” (L. Andersson, J. Davies, R. Duncan, P. Ferruti, J. Ford, S. Kneller, R. Mendichi, G. Pasut, O. Schiavon, C. Summerford, A. Tirk, F. Veronese, V. Vincenzi, and G. Wu. Biomacromolecules, 2005, 6 (2), 914-926). Desai, et al. have reported in U.S. Pat. No. 5,648,506 attaching taxol to 8-arm PEG through urethane and ester linkages, but do not describe thioether or disulfide linkages, nanocarriers, nanogel particles, aggregated nanogel particles, gelation that can occur in vivo, gelation with relatively nontoxic materials, crosslinking of PEG with the PEG not being part of a PEG/nonPEG copolymer, or any aspect of sulfur chemistry. Therefore, although it is desirable to have more than one copy of a drug or agent on a single nanocarrier having acceptable aqueous solubility, and biological characteristics, it has not been achieved to date.